promis neurosciences corporate overview, september 2020 ...€¦ · such information involves known...

ProMIS Neurosciences Corporate Overview, September 2020

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Toronto Stock Exchange (TSX) ticker: PMN OTCQB ticker: ARFXF

Forward looking statement: safe harbor

This slide deck may contain certain forward-looking information. Such information involves known and unknown risks,uncertainties and other factors that may cause actual results, performance or achievements to be materially differentfrom those implied by statements herein, and therefore these statements should not be read as guarantees of futureperformance or results. All forward-looking statements are based on the Company’s current beliefs as well asassumptions made by and information currently available to it as well as other factors. Readers are cautioned not to placeundue reliance on these forward-looking statements, which speak only as of the date of this slide deck. Due to risks anduncertainties, including the risks and uncertainties identified by the Company in its public securities filings availableonline at www.sedar.com. Actual events may differ materially from current expectations. The Company disclaims anyintention or obligation to update or revise any forward-looking statements, whether as a result of new information,future events or otherwise

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http://www.sedar.com/

ProMIS Neurosciences Overview

• ProMIS unique technology platform a competitive advantage- AI platform, precise predictions of antibody targets- Highly efficient discovery process for antibody therapies, diagnostics, vaccines

• Alzheimer’s market at an inflection point- Similar to immuno-oncology 10 years ago- Precipitating factors: first disease modifying therapy approvals, blood-based biomarkers

• ProMIS opportunity to capitalize on Alzheimer’s inflection- PMN310, potential best in class therapeutic antibody; diagnostics JV; therapeutic vaccine

• Potential differentiated COVID serology assay assessing antibody-based immunity

• Broad portfolio - tau (Alzheimer's), TDP43 (ALS), Alpha Synuclein (Parkinson’s)

• Numerous near- and medium-term potential catalysts

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ProMIS unique technology platform: competitive advantage, rapid and cost-effective platform for therapeutic antibodies, diagnostics, and vaccines

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YAntibody

Conformational Epitope

Toxic Protein or virus

Antibodies bind to targets called EPITOPES ( )which have a specific conformation or shape

ProMIS has unique capability to predict epitopes including their shape and make precise replicas – peptide antigens

Peptide Antigen

Antibody Therapy

DiagnosticTherapeutic

Vaccine

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Alzheimer’s Disease: the epidemic of this century

“Will Bankrupt Medicareif Therapy is not developed”

Direct and Indirect Costs Today in the US $500BB….

…. and the number is tripling by 2030….

The goal in Alzheimer’s is prevention – a large and growing market

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Symptomatic AD

~6MM

Population over 60 at risk –86MM in US and Canada

30%- 50% of population over 60

with pathology, pre-symptomatic

~30MM- 40MM

20+ years to develop symptoms, from onset of pathology (neuronal death)

Alzheimer’s is at an inflection point like immuno-oncology ten years ago

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"Neuroscience has the potential to be in the '20s what oncology has been in the last decade."

– Bill Anderson, CEO of Roche Pharmaceuticals (JPM 2020)

Immuno-Oncology

~2000’s

2010 -inflection

- Numerous failures- Skepticism, lack of capital

- First cancer vaccine approved (sipuleucel-T)- First positive clinical data for PD-1 (nivolumab)

2017/2018 - validation

- Gilead acquires Kite (2009 start up) $11.9BB- Celgene acquires Juno (2013 start up) $9BB

The precipitating factors in the Alzheimer’s inflection

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First disease modifying therapies Blood-based biomarkers

Biogen’s aducanumab

- Priority review granted, Aug 7, 2020- Potential FDA approval Q1 2021

Eisai’s BAN2401

- Phase 3 read out anticipated 2022- Potential FDA approval 2022/2023

“Plasma p-tau217 set to transform Alzheimer’sdiagnostics”- ALZFORUM July 29, 2020

Neurofilament light chain (NfL) measures neuronal death,p-tau elevated in AD

Biomarkers enable dramatically more efficientdevelopment programs

Biomarkers enable efficient screening and diagnosis, including pre-symptomatic disease

The “inflection scenario” in Alzheimer’s – ProMIS: TREAT-DETECT-PREVENT

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Approval of first disease modifying therapies

- Biogen aducanumab Q1’ 2021

- Eisai BAN2401 2022/23

Rapid acceleration of diagnostics / screening

market

Identification of millions of pre-symptomatic AD patients

- Prevention Market

PMN310Potential “best in class”

antibody

Diagnostics JV – Accredited Lab- NfL, p-tau

- Proprietary assays

Therapeutic Vaccine- Amyloid-beta, tau

TREAT DETECT PREVENT

PMN310: an anti-Aβ-oligomer antibody with strong potential to demonstrate best-in-class characteristics

Aducanumab and BAN2401 are only partially selective for amyloid oligomers

• Aducanumab (phase 3) and BAN2401 (phase 2) showed modest but meaningful efficacy in reducing cognitive worsening

• Neither bind monomer (the physiologic amyloid species)

• But both significantly bind amyloid plaque → ARIA-E (brain swelling)

PMN310 is a next-generation, best-in-class anti-amyloid therapy• Highly selective for only toxic oligomers

• Dose expected not to be limited by off-target binding or side effects• Does not bind monomer• Does not bind plaque → likely no ARIA-E

• All dosed PMN310 will be focused on neutralizing toxic oligomers → potentially greater clinical efficacy

PMN310 will utilize blood-based biomarkers in initial trials, enabling rapid timeframe and limited capital needs to value-creating clinical data

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Aβ amino acids 13-16 (HHQK)A unique, Aβ oligomer specific

conformational epitope targeted by PMN310

There are three forms of amyloid, PMN310 is differentiated by selective binding of the toxic form (oligomers)

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Aducanumab (Biogen)• Phase 2 & 3 success• ARIA-E side effect

Solanezumab (Eli Lilly)

• Phase 2 failure• Phase 3 failure

Bapineuzumab (Pfizer)• Phase 2 failure• Phase 3 failure• ARIA-E side effect

MONOMERS- binding wastestherapeutic ammunition

FIBRILS (Plaque)- binding wastestherapeutic ammunition- contributes to ARIA-Eside effect

OLIGOMERS*- the right target

PMN310• Selective binding to

oligomers-> Expected improvement in

efficacy & safety

* Synthetic oligomers

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ARIA-E associated with aducanumab, BAN2401 & bapineuzumab; PMN310 lack of binding to Aβ plaque strongly suggests a potential safety advantage

Aducanumab PMN310

Plaque binding

Vascular deposit binding

No binding to plaque or vascular deposits

Most likely no ARIA-E*

* ARIA-E (Amyloid Related Imaging Abnormality-Edema) also known as brain swelling

Hum

anized

PM

N31

0

Aduca

numab

Bap

ineu

zum

ab

huIgG1

0

10

20

30

40

50B

ind

ing

Resp

on

se (

RU

)

PMN310 shows superior binding to toxic oligomers from human AD brains vs other antibodies directed against amyloid-beta

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• Binding of antibodies to the toxic oligomer-enriched LMW fraction of soluble human AD brain extract was evaluated by surface plasmon resonance (SPR)

• Results representative of over 10 SPR runs with extracts from 11 different AD brains

• huIgG1 = Background control

Source for comparative reagents: Creative Biolabs

AbO +/- MabNovel Object Recognition Assay

• Control mice remember a familiar object when re-exposed to it and spend more time exploring a new object

• Oligomer-injected mice lose the ability to discriminate between known and novel objects and spend equivalent amounts of time exploring both

7 days

-0.2

0.0

0.2

0.4

0.6

Vehicle AβOPMN310+ vehicle

PMN310+ AβO

Dis

crim

inat

ion

Ind

ex

#

* *

Discrimination index = (Time exploring new object – time exploring familiar object) / total exploration timeResults press released January 9, 2017, www.promisneurosciences.com 14

N=12 per arm, *different from AβO (p < 0.05), #different from vehicle (p <0.05)

Administration of PMN310 to mice prevents loss of short-term memory formation caused by toxic oligomers, by saving mouse neurons

THE RESULTSTHE EXPERIMENT

• Mice are tested for discriminating objects after brain injection of:

• Buffer (vehicle) - normal response

• Toxic Aβ oligomer

• PMN310 and buffer (vehicle)

• PMN310 and Aβ Oligomer

Clinical results in the amyloid field confirm the need for targeting the toxic form of amyloid……

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Monomer – Important for brain health

Toxic oligomers –thousands of scientific

studies showing neurotoxicity

Two Programs – BOTH POSITIVE. Biogen’s aducanumab, Eisai’s BAN2401Both with dose-limiting side effect ARIA-E* related to plaque binding

* ARIA-E (Amyloid Related Imaging Abnormality- Edema) also known as brain swelling


Plaque – usually present, but no significant role in

disease




PlaqueUsually present, but no

significant role in disease



MonomerImportant for brain

health

Toxic oligomers Thousands of studies showing neurotoxicity

4 programs All negative

10 programsAll negative

Forms of Amyloid

AmyloidBinding

profile of clinical

programs

ProMIS PMN310Selective Binding = Best

in Class Profile

PMN310: potential for value-creating clinical data in the near term - likely positive market developments could amplify PMN value

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ProMIS Final IND enabling work

2020

AD in Down Syndrome - prevention, treatment, or both: Biomarker and

clinical endpoint readout

Sporadic AD Phase 1: 3 month Pbo control, 9 month extension, MAD design

2021 2022

Potential Approval Path:AD in Down Syndrome

AducanumabFiling

AducanumabApproval

Aducanumab Launch and Market DevelopmentBAN2401Ph 3 data

• Recent advances in blood-based biomarkers may allow ProMIS to detect an objective treatment signal as early as Phase 1, potentially providing rapid & cost-effective proof-of-concept

ProMIS/BCNI Joint Venture to build a diagnostic revenue base in Alzheimer’s

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Historical: AD diagnosis at autopsy

Recent advance:A/T/N

Amyloid PET

Tau PET

Cortical MRI

Future: blood based diagnostics

NfL Blood-based

p-tauBlood-based

Significant recent advances in AD screening and diagnosis

ProMIS/BCNI Joint Venture to build a diagnostic revenue base in Alzheimer’s

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Historical: AD diagnosis at autopsy

Recent advance:A/T/N

Amyloid PET

Tau PET

Cortical MRI

ProMIS / BCNI diagnostics vision

NfL Blood-based

p-tauBlood-based

Significant recent advances in AD screening and diagnosis

Differential diagnosisTDP43, Alpha-Syn

Other proprietary assays, algorithms

• JV with BCNI, accredited diagnostics lab• Enables rapid monetizing of proprietary

diagnostics based on ProMIS platform • Strategy: combine proprietary assays with

emerging standards like p-tau, create a differentiated offering

ProMIS therapeutic vaccine for Alzheimer’s disease

• Growing number of individuals in the pre-symptomatic phase of the disease (potentially 40% of the population over 65, ~50M) –> Prophylactic preventative vaccine

• Vaccine approach will benefit from recent progress in the development of blood-based biomarkers of neurodegeneration to diagnose AD and identify individuals at risk of developing disease

• ProMIS discovery platform being applied to devise a safe & effective vaccine to induce a specific immune response against toxic Ab oligomers

• Identified a set of 6 conformational peptide epitopes selectively exposed on toxic Ab oligomers

• All 6 peptide epitopes shown to be capable of inducing selective and protective antibodies against toxic Ab oligomers

• Successful proof of concept vaccination study conducted with one of the peptides (cSNK) in a mouse model of AD (APP/PS1 mice): Neuronal protection and improvement in cognitive deficits2

• Concept: multivalent vaccine with some or all 6 Ab peptides. Tau peptides recently identified could also be included.

• Immediate aims: construct and test multivalent Ab vaccine for ability to induce a protective antibody response

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1Marciani DJ, 2019, AAAS Research, https://doi.org/10.34133/2019/5341375; 2Silverman, JM et al, 2018, ACS Chem Neurosci

https://doi.org/10.34133/2019/5341375

Initial pilot results confirm benefit of vaccination with ProMIS Ab oligomer (AbO) epitope

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Mice vaccinated with conformational Ab oligomer epitope (cSNK) coupled to KLH

Robust, sustained antibody response

(SPR)

Improvement in behavioral deficits of APP/PS1 mice

Protection against synaptic damage

Silverman et al. 2018. ACS Chem Neurosci

The “inflection scenario” in Alzheimer’s – ProMIS: TREAT-DETECT-PREVENT

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Approval of first disease modifying therapies

- Biogen aducanumab Q1’ 2021

- Eisai BAN2401 2022/23

Rapid acceleration of diagnostics / screening

market

Identification of millions of pre-symptomatic AD patients

- Prevention Market

PMN310Potential “best in class”

antibody

Diagnostics JV – Accredited Lab- NfL, p-tau

- Proprietary assays

Therapeutic Vaccine- Amyloid-beta, tau

TREAT DETECT PREVENT

COVID Serology assay: ProMIS goal to create assay that can assess antibody-based immunity

• Serology assays measure antibodies, antibodies indicate “exposure” to COVID-19, but not all antibodies to COVID-19 have neutralizing effect

• ProMIS goal to create assay that correlates with gold standard measure of neutralizing activity, assessing antibody-based immunity

• Progress to date:- Digital Supercluster grant in May- Announced data on “exposure” assay, 99+% sensitivity and specificity late June- Ongoing assessment with proprietary reagents to develop assay indicative of antibody immunity

• Numerous commercialization options if successful:- Government contract, vaccine manufacturer deal, license reagents to diagnostics companies

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Abbott CEO Robert Ford in FORBES, July 17“As vaccines become available, we would anticipate continued surveillance testing to monitor and assess for both natural and vaccine related immune response, which would be followed by a steady state of ongoing monitoring and tracking of vaccineprotection…..that’s where I think we will see an increase in serology and antibody testing. I see that that’s going to be an

opportunity for us and other companies that have the antibody test, I see that as being a real demand driver on the serology side”

Numerous near and medium-term potential catalysts

• Neurodegenerative disease diagnostic/screening • Data on proprietary assays

• Regulatory approvals

• Revenue

• COVID serology diagnostic • Data on proprietary assays

• Regulatory approval

• Revenue

• Biogen aducanumab approval Q1 2021

• Partnering

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ProMIS Summary

• Unique proprietary technology platform – rapid, cost-effective, differentiated

• Strategic portfolio in Alzheimer’s based on unique platform – Detect – Treat – Prevent

• PMN310 scientifically superior to likely “first in class” therapy Biogen’s aducanumab, PMN310 selective for toxic oligomers, stronger binding

• Biogen granted Priority Review by the FDA, potential Q1 approval and launch will be strong catalysts for the field, especially improved amyloid targeted therapies like PMN310

• ProMIS’ broad portfolio, programs targeting mis-folded versions of TDP43, alpha-synuclein, tau, ongoing partnering discussions (timing affected by industry priority shift to COVID, lab closures, etc.)

• Aducanumab launch will also likely lead to dramatic growth in demand for screening and diagnosis of dementia

• ProMIS JV with BCNI will enable capitalizing on that growing demand with both established and proprietary assays

• ProMIS technology enables potential Alzheimer’s vaccine – building on early POC

• Rapid response to COVID-19; goal to create differentiated immunity serology assay, potential near-term revenue if successful

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Thank You

Eugene Williams, Executive [email protected]+1 (617) 460-0978

Website: www.promisneurosciences.comTwitter: https://twitter.com/ProMISincLinkedIn:https://www.linkedin.com/company/promis-neurosciences

Please feel free to contact us with any additional questions.

Elliot Goldstein, MD, [email protected]+1 (415) 341-5783

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APPENDICES

• ProMIS portfolio – highly selective antibodies for mis-folded protein diseases

• Background on the amyloid-beta field; science and clinical results

• Biomarkers, biomarker-based trial designs

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ProMIS: current portfolio of antibodies selectively targeting toxic mis-folded proteins

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Scientific Literature:Mis-folded protein role

in disease pathogenesis;

role of other forms (molecular species)

Predict conformational

epitopes on target molecular species

Immunize and screen antibody candidates

for selectivity

Assess functional benefit in vitro and in vivo; assess binding strength to enriched patient biomaterial

IND enabling development

Biomarker readouts of pharmacologic

effect in Ph1

Predict Produce Prioritize Lead program early POC

Amyloid betaPMN310, ready for final

IND enabling work

Alpha Synuclein

Several leads, active partnering discussions

TDP43Several leads, active

partnering discussions

tau Early leads, immunization ongoing , active partnering discussions

Many ongoing discovery: DISC1, FUS, SOD1, Amylin, PrP, other

Neurodegenerative diseases: in need of disease modifying therapy attacking the root cause

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Disease Modifying Therapy

No Therapy“Marginal”

Symptomatic TherapyEffective Symptomatic

Therapy

Alzheimer’s$15BB-$25BB

Peak sales potential..*

ALS

Parkinson’s$4BB-

$6BBPeak sales potential..*

FTD

CTE

LBD

FTD = Frontotemporal dementiaLBD = Lewy Body dementiaCTE = Chronic traumatic encephalopathy

• Analysis by Centerline: assumes market average penetration, diagnosis, 40% mkt share

None

ALS(TDP43, SOD1, FUS)

Parkinson-like diseases(alpha-synuclein)

Alzheimer’s disease(amyloid-beta and tau)

Prion diseases(prion protein)

Huntington’s disease (huntingtin)

Senile amyloidosis (transthyretin)

Schizophrenia(DISC1)

Type 2 diabetes(amylin)

Mis-folded proteins are the root cause of multiple disorders

5

http://diabetes.diabetesjournals.org/content/56/4/930/F1.large.jpg


ALS(TDP43, FUS, SOD1)

Parkinson-like diseases(alpha-synuclein)

Alzheimer’s disease(amyloid-beta and tau)

Huntington’s disease (huntingtin)

Senile amyloidosis (transthyretin)

Schizophrenia(DISC1)

Type 2 diabetes(amylin)

The same proteins perform essential cellular functions when in their normal, physiological form

Synaptic Remodeling

Neuron Stability

DNA Repair

Synaptic Remodeling

DNA repair

Normal forms play critical role in brain

health

RNA Splicing, Transport

DNA Repair

6



The key to disease modifying therapy in neurodegenerative disease….the ProMIS strategy

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Neutralize the toxic mis-folded form

Don’t interfere with the normal form, critical for

brain health

ProMIS has an unmatched track record creating selective antibodies accomplishing that goal…..

Targeting the toxic species of alpha-synuclein for Parkinson’s disease and related

syndromes

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Alpha-synuclein is the major driver of Parkinson’s disease, Multiple System Atrophy (MSA) and other synucleinopathies

• Synucleinopathies: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of

dopaminergic neurons located in the midbrain and the presence of intraneuronal inclusions (Lewy bodies/Lewy

neurites) consisting mainly of aggregates of a-synuclein (a-syn). Accumulation of insoluble a-syn fibrils in the

brain is also observed in dementia with Lewy bodies (LBD) and multiple system atrophy (MSA).

• Genetic mutations (A53T, A30P, E46K, H50Q, G51D) and duplications/triplications of the a-syn gene cause

inherited familial PD1

• Polymorphisms in the a-syn gene and its promoter are associated with an increased risk of sporadic PD1

• Mice injected with aggregated a-syn from diseased patient brains develop synucleinopathy-like pathology and

symptoms2

• Aggregated a-syn propagates from cell to cell in a prion-like manner in cell culture3 and

in animals4,5 mimicking disease progression in patients

1Reviewed in Vaikath, NN et al, J Neurochem 2019; 2Reviewed in Karpowicz Jr, RJ et al, Lab Invest 2019; 3Choi et al, Cell Reports 2018; 4Peelaerts et al, Nature, 2015; 5Fourla JM et al, JBC 2019

Braak, H et al, Neurobiol of Aging, 2003

Therapeutic imperative: selectively target only the toxic a-synuclein aggregates

• Alpha-synuclein exists in different forms including normal,

physiologically important conformations and toxic forms:

• Monomers play an important role in the regulation of synaptic vesicle trafficking and release as well as neuronal survival1

• Physiological a-syn tetramers inhibit aggregation and must be preserved for healthy a-syn homeostasis2-4

• Lewy bodies consisting of insoluble a-syn are a marker of disease but unlikely to have direct neurotoxicity5

• Recent evidence indicates that a-syn toxicity resides primarily with soluble oligomers6,7

• Progression of disease is likely mediated by oligomers and small soluble fibrils of a-syn that have been shown to propagate from cell to cell in a prion-like manner in vitro8 and in vivo9

• Maximal efficacy and safety is expected to require selectivity

for the toxic forms of a-syn, oligomers and/or small soluble

fibrils, while avoiding physiologic forms of a-syn

1Lashuel HA et al, Nat Rev Neurosci, 2013; 2Nuber et al, Neuron, 2018; 3Dettmer et al, PNAS, 2015; 4Foulds et al, Scientific Reports, 2013; 5Vaikath NN et al, J Neurochem 2019; 6Fusco et al, Science, 2017; Desplats P et al, PNAS, 2009; 8Choi et al, Cell Reports, 2018; 9Peelaerts et al, Nature, 2015

OptimumTherapeuticProfile

Avoidphysiologictetramer

AvoidMonomer

TargetToxicOligomers

TargetSolubleFibrils

Minimizetargetingnon-toxicoligomers

MinimizetargetingLewy

Bodies

ALPHA-SYNUCLEINProMIS’ unique technology platform has created antibodies that achieve the targeted binding profile….better than other a-synuclein-directed antibodies

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Target Properties PMN Antibodies

Prothena/Roche

BioArctic/ABBVIE

Neurimmune/Biogen

No binding to monomers ✔️ X +/- X

No binding to physiological tetramers

✔️ X +/- X

Binding to oligomers/small soluble fibrils

✔️ ✔️ ✔️ ✔️

Binding to native toxic a-synin LBD/PD brain extract

✔️ ✔️ ✔️ ✔️

Little or no binding to insoluble fibrils (Lewy bodies)

✔️ X X X

ProMIS antibodies protect dopaminergic neurons against a-synuclein oligomer toxicity in vitro

36*p<0.05, **p<0.01 vs a-syn oligomers alone

Contr

ol

a-sy

n olig

o

9D8

+ a-

syn (1

:2)

12G1

+ a-

syn (1

:2)

12B12

+ a

-syn

(1:2

)

8B12

+ a

-syn

(1:2

)

7F6

+ a-

syn (1

:2)

10D5

+ a-

syn (1

:2)

BDNF

40

60

80

100

120

Su

rviv

al (d

op

am

inerg

ic n

eu

ron

% o

f o

cn

tro

l)

***

***

** ****

PMN antibodies

• Multiple antibodies provide neuroprotection in the same range as the brain-derived neurotrophic factor (BDNF) positive control

• As expected, antibodies alone had no effect on viability (not shown)

CONTROL

a-SYN OLIGOMERS

PMN ANTIBODY + a-SYN OLIGOMERS

Normal neurons in bright red

Neurons killed by toxic oligomers

Neuronal death blocked by PMN antibody

ProMIS antibodies inhibit a-synuclein propagation: decreased recruitment of endogenous rat a-syn into pathogenic phosphorylated aggregates

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Human PFF +/- PMN antibody

Rat neurons Rat neurons

14 days

Staining for rat phosphorylated a-syn aggregates

Contr

olPFF

PFF +

12B

12 (0

.05u

M)

PFF +

3C11

(0.0

5uM

)

PFF +

11B

6 (0

.05u

M)

0

50

100

150

200

250

300

* *

PMN antibodies + PFF

*

*p<0.05 vs fibrils alone (PFF)

ProMIS antibodies significantly decrease recruitment into a-syn phosphorylated aggregates

CONTROL a-SYN SOLUBLE FIBRILS a-SYN SOLUBLE FIBRILS + PMN ANTIBODY

Endogenous rat phospho-aggregates stained yellow (denoted by arrows)Human a-syn aggregates stained red

Multiple system atrophy (MSA) as a disease indication for therapeutic antibodies targeting toxic species of a-synuclein

• MSA is a rare neurodegenerative disease with an estimated prevalence of 3.4-4.9 cases per 100,000 population1

• MSA is characterized by rapidly progressive autonomic failure and motor symptoms with predominant parkinsonian features (MSA-P) or dominant cerebellar features (MSA-C)1,2

• There is no effective treatment and the mean survival from the onset of symptoms is 6-10 years1,2

• Histologically characterized by a-synuclein aggregates in the cytoplasm of oligodendrocytes and to a lesser extent in neurons and other glial cells1,2

• Alpha-synuclein aggregates from MSA brain homogenates propagate in a prion-like manner in vitro3 and in vivo4 and cause MSA-like neurodegeneration in mice5

• Suitability for clinical testing:• Rapid progression allows for earlier efficacy signal

• High levels of NfL in serum represent a potential biomarker for effect on neuronal damage – early clinical PoC

• No placebo effect observed in clinical trials to date

• Rare disease but easy recruitment due to unmet need and existence of a global MSA Registry (GLOMAR) and supporting organizations1,2

381Fanciulli A & Wenning GK, 2015, NEJM; 2Krismer F & Wenning GK, 2017, Nature Neurol; 3Krejciova Z et al, 2019, Acta Neuropathol Comm; 4Watts JC et al, 2013, PNAS; 5Bernis ME et al, 2015, Acta Neuropathol Comm

a-syn glial cytoplasmic inclusions (GCI)2

Day 7 Day 14 Day 21

In vitro propagation of MSA a-syn aggregates3

Potential development plan for alpha-synuclein program: early proof of concept with an antibody; rapid route to approval with a gene therapy in MSA

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Final IND enabling work• Alpha-synuclein

antibody – IgG1

IND enabling for gene therapy (vectorized version of antibody)

MSA patient Phase 1: multiple ascending dose (MAD) design

Pivotal trial program in MSA - seeking regulatory approval

Potential approval pathway: gene therapy with vectorized antibody in MSA- Gene therapy development in rare, progressive and fatal disease can be rapid, possibly “one and done”- Monoclonal antibody provides initial clinical proof of concept – safety and biomarker evidence of efficacy

Antibody

Gene Therapy

Vectorize lead antibody

In gene therapy

ProMIS alpha-synuclein program: Summary

• Scientific literature suggests a complex binding profile for an optimum antibody

• Bind toxic oligomers and small soluble fibrils involved in propagation

• Avoid physiologic monomer and tetramer to reduce adverse event odds, enable vectorization

• Minimize binding to inert soluble aggregates and Lewy bodies to maximize therapeutic dose available

• ProMIS used its unique antibody design platform, identifying unique epitopes presented on target molecular species, to generate multiple antibody candidates with the target binding profile and the ability to inhibit a-syn neurotoxicity and propagation in vitro

• Multiple antibody candidates with potential competitive advantages over therapies in development – better selective binding profile may lead to better clinical outcomes and is critical to enable vectorization, a top priority for large pharma potential partners

• MSA as an early clinical proof of concept indication may show a positive treatment effect in the first trial – patients are rapidly progressive with elevated biomarkers at baseline

40

Targeting toxic species of TDP43for ALS

41

Prion-like propagation of mis-folded TDP43 is a driver of pathogenesis in ALS and frontotemporal lobar degeneration (FTLD)

• Mis-folded protein aggregates of TDP43 are a pathological hallmark of ALS and FTLD1

• The stereotypical distribution of TDP43 pathology in ALS and FTD shows a spreading pattern consistent with progressive dissemination from neuron to neuron2,3

• Mis-folded aggregates of TDP43 are toxic to neural cells4,5

• Prion-like cell to cell propagation of TDP43 aggregates has been demonstrated in cell culture5,6 and animal models7

• Mis-folded TDP43 induces misfolding of other proteins into pathogenic aggregates (e.g. SOD18, nuclear pore proteins and transport proteins9, DISC110 , RACK111 – “TDP43 Pathological Interactome”

1Neumann et al, 2006, Science; 2Braak et al, 2013, Nat Rev Neurol; 3Brettschneider et al, 2014, Acta Neuropatholl; 4Wang et al, 2016, Nat Med; 5Nonaka et al, 2013, Cell Reports; 6Feiler et al, 2015, J Cell Biol; 7Porta et al, 2018, Nature Commun; 8Pokrishevsky et al, 2016, Scientific Reports; 9Chou et al, 2018, Nat Neurosci; 10Endo et al, 2018, Biological Psych, 11Russo et al, HMG 2018.

Mis-folded SOD1 (green) in primary spinal cord cultures exposed to supernatant from HEK293 cells transduced with TDP43DNLS

(misfolded) but not empty vector

Induction of SOD1 mis-folding by pathogenic TDP438In vivo spreading of TDP43 pathology from site of injection7

Empty vector sup TDP43DNLS sup

ProMIS antibody against TDP43 is selective for mis-folded TDP43

Confocal microscopy of HEK293 cells

transduced with misfolding

TDP43DNLS with HA tag

Cytoplasmic mis-folded TDP43 (stained for HA tag)

PMN antibody: No staining of WT nuclear TDP43, staining of mis-folded cytoplasmic TDP43 (co-localization in merged images)

Staining of frozen sections from FTD

brain and ALS spinal cord

Performed by Dept. of Pathology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands

Grey matter – FTD type A Grey matter – FTD type E ALS spinal cord

Scale bars represent 50 mm

Potential development plan for TDP43 program: early proof of concept with an antibody; rapid route to approval with a gene therapy in ALS

44

Final IND enabling work• TDP43 antibody, IgG1

IND enabling for gene therapy (vectorized version of antibody)

ALS patient Phase 1: multiple ascending dose (MAD) design

Pivotal trial program in ALS - seeking regulatory approval

Potential approval pathway: Gene therapy with vectorized antibody in ALS- Gene therapy development in rare, progressive and fatal disease can be rapid, possibly “one and done”- Monoclonal antibody provides initial clinical proof concept – safety and biomarker evidence of efficacy

Vectorize lead antibody

In gene therapy

Antibody

Gene Therapy

Summary of mis-folded TDP43 antibody findings

• Multiple antibodies generated with epitope binding affinity in the sub-nanomolar range

• Antibodies identified with reactivity and specificity for aberrant cytoplasmic TDP43 aggregates in

cell model, and no reactivity with wild-type nuclear TDP43 -> preserves normal, essential TDP43

function

• The same antibodies do not show binding to physiological stress granules -> preserves stress-

protective function

• Staining of TDP43 in human frontotemporal dementia (FTD) and ALS samples confirms reactivity

with native pathological TDP43

• Potential for rapid proof of concept in the clinic in ALS

• ProMIS selectivity advantages critical for gene therapy vectorization; gene therapy in ALS could be

enable a rapid route to approval; strong interest from potential pharma partners in vectorization

45

APPENDICES




46

Updating the amyloid hypothesis in light of aducanumab pivotal trial data: amyloid matters & ProMIS is on the right track targeting toxic AβOs

• There is no question that amyloid plays a role in AD pathology

• Icelandic population with APP mutation, unable to make amyloid never develop AD, while Down syndrome patients who make too much amyloid always develop AD, nearly 100% exhibit AD pathology by age 40

• The Biogen aducanumab pivotal dataset is the best dataset to date in AD shedding light on what can modify the course of disease. The data say the answer is YES, neutralizing amyloid can provide clinical benefit in symptomatic patients.

• Biogen ran two pivotal trials, the data were less clear than we would have liked due to two management decisions:

• starting the pivotal with 2/3 of the patients receiving a suboptimal high dose (6mg instead of 10mg); and then

• after adjusting mid-trial through a protocol amendment (V4), failing to account for that change in a pre-planned futility analysis and stopping the trial in March 2019.

• At CTAD, Biogen presented an analysis of only the V4 subset of patients, those who consented to the protocol dose increase.

Those data are probably most representative of what will happen in the real world if/when aducanumab is approved. It will be

used at 10mg/kg. In the V4 subset, both pivotal trials showed a meaningful slowing of clinical progression by 30% and 27%

respectively, with a ~30% rate of the ARIA-E side effect. It is unfortunate that both pivotal trials were not run from the

beginning and completed with a high dose of 10mg (as per the V4 amendment), but this is is still the best data to date in

providing some insight into how to slow progression of AD

47

Updating the amyloid hypothesis in light of aducanumab pivotal trial data: aducanumab is approvable, PMN 310 designed to be “best in class”

• Aducanumab differs from all failed programs in that it does not bind the simplest form of amyloid - monomer. It only binds aggregated forms, oligomer and plaque (like EISAI’s BAN2401, which also had a positive Phase 2 study with a dose-dependent slowing of progression).

• That raises the question - which of the two (oligomer or plaque) is the disease culprit? The data are overwhelming that the culprit is the oligomer. Thousands of studies have been published evaluating what forms of amyloid are toxic to neurons - oligomers are toxic, plaque is not.

• Biogen in their aducanumab Nature publication in 2016 suggested that clinical benefit might come from neutralizing oligomers

• In the aducanumab pivotal program, plaque reduction was not correlated with clinical benefit - the full dataset from one pivotalENGAGE, showed no clinical benefit despite the same level of plaque reduction as the EMERGE pivotal that did show benefit.

• All studies of aducanumab and BAN2401 have shown a strong dose response with only the highest doses showing clinical benefit, suggesting that delivery of a higher dose would increase efficacy.

• But both products have reached their maximum tolerated dose, due to ARIA-E side effect associated with plaque binding

• Based on all clinical and scientific data to date, a product that avoids plaque binding while strongly binding only Aβ oligomers would likely have greater clinical benefit vs. aducanumab V4 data, with little/no side effect

• PMN310 is that potentially best in class product

48

49

Billions of neurons are killed leading to the Alzheimer’s brain on the right………toxic amyloid is a root cause

1 Reviewed in Bloom 2014, JAMA Neurol

Healthy BrainBrain with

Mild Cognitive ImpairmentBrain with AD1

15 years pre-symptomatic 5 years MCI 10 years Alzheimer’s

Toxic, mis-folded amyloid plays a role throughout disease

Toxic, mis-folded amyloid hyperphosphorylates tau

Neuroinflammation exacerbates disease

Icelandic Genetic mutation:

No amyloid No AD

Down Syndrome: Excess amyloid

Early, High % AD

Alzheimer’s disease: soluble toxic Aβ oligomers – not plaque or

monomers – are the most neuropathogenic Aβ species

• Synapse abnormalities and memory impairment correlate poorly with plaque burden in human and mouse AD1,2

• Aβ monomers and Aβ insoluble fibrils (plaque) have little or no demonstrable toxicity in vitro or in vivo3-5

• Soluble Aβ oligomers show the highest degree of neurotoxicity6

• Toxicity in primary neuron cultures and brain slices3,5,7-9

• Induction of cognitive impairment in rodents3,4,10

50

1Jacobsen et al, 22006, PNAS; 2Brier et al, 2016, Science Trans Med; 3Shankar et al, 2008, Nature Med; 4Cleary et al, 2005, Nature Neuroscience; 5Hong et al, 2016, Science; 6Benilova et al, 2012, Nature Neuroscience - Review; 7Lacor et al, 2007, J Neuroscience; 8Jin et al, 2011, PNAS; 9Lauren et al, 2009, Nature; 10Balducci et al, 2010, PNAS

Synaptotoxicity of human Ab oligomers on hippocampal neurons in vitro7

5min 6h 24h 24h control

Monomers Oligomers Fibrils

Normal Monomers Oligomers Fibrils

Ab species injected

In vivo impairment of recognition memory by Ab oligomers, not monomers and not fibrils10

Clinical results in the amyloid field confirm the need for targeting the toxic form of amyloid……

51




Two Programs – BOTH POSITIVE. Biogen’s aducanumab, Eisai’s BAN2401Both with dose-limiting side effect ARIA-E* related to plaque binding

* ARIA-E (Amyloid Related Imaging Abnormality- Edema) also known as brain swelling


Plaque – usually present, but no significant role in

disease




PlaqueUsually present, but no

significant role in disease



MonomerImportant for brain

health

Toxic oligomers Thousands of studies showing neurotoxicity

4 programs All negative

10 programsAll negative

Forms of Amyloid

AmyloidBinding

profile of clinical

programs

ProMIS PMN310Selective Binding = Best

in Class Profile

Aducanumab provides clinical benefit of 20% - 30% only at the highest dose, 10mg/kg - strong dose response curve

PRIME Phase 1B -52 wks

CDR -SB

p<0.05

Placebo 3mg 6mg *10mg

V4 pivotal high dose -72 wks

52

EMERGE ENGAGE

High dose (n=288)

10mg/kg

Difference v. placebo

P<0.01

CDR-SB

Treatment effect -30%

High dose (n=282)

10mg/kg

Difference v. placebo

P<0.01

CDR-SB

Treatment effect -27%

A product that could dose higher for the oligomer – with no plaque binding, likely to have better outcomes……….

*Treatment effect: -22%

Four positive trials…partially selective antibodies…higher dose over long duration leads to better outcomes, but all limited by brain swelling (ARIA-E)

53

Biogen Ph1b “PRIME” December 2014

Eisai BAN2401 Phase 2July 2018

Biogen pivotal EMERGEDec 2019*

Biogen pivotal ENGAGEDec 2019**

* Final Intent-to-treat data set ** Post-protocol version 4 data set

APPENDICES




54

Clinical Development Strategy at ProMIS: summary of key points

Pursue rapid, cost-effective development of our assets that creates an early inflection point in program value

55

Utilize innovative, informative fluid-based biomarkers to rapidly show a disease-modifying treatment effect

NfL, GFAP, p-181Tau (plasma)

Neurogranin, SNAP25, YKL-40 etc (CSF)

Focus on disease populations in each program that have the highest odds of showing a biomarker response in an early, relatively small clinical study

Anti-alpha-synuclein Multiple System Atrophy Anti-amyloid beta AD in Down Syndrome Anti-TDP-43 Amyotrophic Lateral Sclerosis

The impressive, recent development of fluid-based biomarkers represents a revolutionary advance in the development of drugs for neurodegenerative disorders and one that will quickly accelerate the assessment of

disease-modifying therapies in early phase clinical development

56

Neurodegenerative disease drug R&D: we’re in the midst of a biomarker revolution!

22

Neurofilament light chain (NfL) is a measure of the rate of neuronal death, a hallmark of neurodegenerative diseases…..

57

NfL

Blo

od

Lev

el (

pg

/ml)

60

40

20Normal

Pathological

MCI

FTD/ALS

AD

Sources: from AAIC 2018 ABBVIE, Wash U, U Sorbonnne; Rohrer et al, 2016 AAN; Mattson et al, JAMA Neurology 2017

From JAMA Neurology, April 22 2019

“ The findings suggest that plasma NfL can beused as a noninvasive biomarker associated with neurodegeneration in patients …and may be useful to monitor effects in trialsof disease-modifying drugs”

Mattsson, et al, JAMA Neurology

MSA

MCI – Mild cognitive impairment; AD – Alzheimer’s disease; MSA – Multiple system atrophyFTD – frontotemporal dementia, ALS – Amyotrophic lateral sclerosis

NfL has proven to be a valuable pharmacodynamic marker in multiple sclerosis and SMA (spinal muscular atrophy)

58

Neurofilament light in cerebrospinal fluid following monthly administration of natalizumab (300 mg) in 92 patients with multiple sclerosis

Gunnarsson, et al Annals of Neuro 2011Winter B. et al, J Neurol Neurosurg Psychiatry 2019

Tysabri in multiple sclerosis Spinraza in spinal muscular atrophy

Phase 1 trial design concept: in higher dose arms, biomarkers can give

a signal suggesting therapeutic benefit early in clinical development

59

0.3mg/kg - HNV

Dose Escalation Design

1 mg/kg – HNV/AD patients

3 mg/kg –AD Patients




3-month placebo-control, then 9-month open-label extension

Growing list of predictive biomarkers under development

to consider

HNV = healthy normal volunteers


Dose levels are representative examples, drawn from other neurodegenerative monoclonal antibody programsPossibility to use HNVs in lower dose arms, or as sentinel subjects in each cohort

Hypothetical example – Phase 1 biomarker readout could show a disease-modifying treatment effect in a dose-dependent fashion at a cost of $5MM-$10MM

60

BloodNfL

100*

* 100 = patient baseline value

Months1260

Placebo/ Large natural history dataset

3 mg/kg

10 mg/kg

20 mg/kg

40 mg/kg

80 mg/kg

Placebo dataset as an historical control

Potential for meaningful datain 6-12 months…

for $5MM-$10MM

Potential biomarkers:

NfL – Neuronal Loss

GFAP – Astrocyte activation

Neurogranin, SNAP25 –Synaptic loss

YKL-40 - Neuroinflammation

Dose escalation design: 3-month placebo-control, then 9-month open-label extension

The clinical proof of concept (POC) for ProMIS amyloid-beta program PMN310 will be Alzheimer’s Disease in Down Syndrome

61

Neurofilament light (NfL) concentration by age and dementia status of individuals with Down syndrome

• Caused by a third copy of chromosome 21 (extra copy of the amyloid precursor protein)

• Associated with physical growth delays, moderate intellectual disability and characteristic facial features

• Almost all people with Down syndrome have amyloid brain deposits by age 40; the majority will show AD symptoms in their 50’s and 60’s and ultimately develop dementia

• Highly motivated DS community for clinical research; established clinical network of research sites (US and EU).

• NfL is elevated in DS and increases rapidly after age 40

• Presymptomatic DS patients with elevated NfL identified and available for interventional studies

PMN310, the ProMIS lead candidate, has highly selective binding to the toxic form of amyloid-b and strong binding

to brain tissue from patients who died of AD

The clinical proof of concept (POC) for ProMIS alpha synuclein program will be Multiple System Atrophy (MSA)

62

Marques, TM, et al. NEUROLOGY 92(13) March 2019

• Aggressive, rare neurodegenerative disease driven by toxic-misfolded, aggregated forms of α-synuclein

• Attacks oligodendroglia and neurons• One of several synucleinopathies (others include PD and LBD)• Symptoms: autonomic dysfunction, parkinsonism and

cerebellar ataxia• NfL markedly elevated

Serum NfL highly discriminates atypical parkinsonism disorders (including MSA) from Parkinson disease or healthy controls

N=29 (22 – MSA, 7 – PSP)

ProMIS has multiple antibodies with highly selective binding to the toxic form of α-synuclein and strong binding to brain tissue from patients who died of MSA. ProMIS is in active

partnering discussions with large Pharma

Multiple System Atrophy

The clinical proof of concept (POC) for ProMIS TDP43 program will be Amyotrophic Lateral Sclerosis

63

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis (ALS)

• Aggressive disease that causes the death of neurons controlling voluntary muscles

• Characterized by stiff muscles, muscle twitching, muscle weakness and atrophy, difficulty with speaking or swallowing

• Majority of sporadic ALS patients (up to 97%) have brains containing TDP-43 protein deposits at autopsy, suggesting its pivotal role in ALS; the current thinking is that TDP-43 pathologic oligomerization and aggregation leads to these deposits

• Serum NfL markedly elevated

• Highly motivated patients for clinical research

• Well established clinical trial networks in the US and EU

ProMIS has multiple antibodies in preclinical development with highly selective binding to the toxic form of TDP-43 and strong binding to brain tissue from patients who died of ALS. ProMIS is in active partnering discussions with large pharma.

A new development paradigm for Alzheimer’s and other neurodegenerative diseases using biomarkers will dramatically improve cost, risk….and time to success

64

Old Development Model

Preclinical models

Phase 2 studiesCan you trust the data?

Phase 3 studies “Open the envelope”

New Model

Preclinical models based on toxic oligomer neurotoxicity

- in vitro, in vivo

Phase 1 studies with biomarker - initial POC

Phase 2 studies with biomarker and clinical POC

Dramatically accelerated

feedback loop

10– 15 years

$1BB

To learn the target waswrong…

2-3 years

~$20MM toSignal of effect

Phase 1 studiesSafety only

Name

Experienced leadership team

30

Prior ExperienceTitle Years of Experience

Executive Chairman

CEO

Chief Science Officer

Chief Physics Officer

CFO

Chief Development

Officer

25+

25+

25+

20

25+

25+

Former SVP at Genzyme, with senior roles integrating commercialization, drug

development, and deal making

Recently the CEO of Dart Therapeutics, an Orphan Disease drug development

company

Founder and director of Adheris, which became the largest company in the

patient adherence/compliance area

Held positions as SVP of Strategic Product Development at SmithKline

Beecham (now GSK)

Chief Operating Officer and Chief Medical Officer of Maxygen Chief Operating Officer at DART Therapeutics

Holds the Canada Research Chair in Neurodegeneration and Protein

Misfolding Diseases,

Serves as the Director of the University of British Columbia ALS

Centre,

Awarded the Jonas Salk Prize for biomedical research in 2000

Professor at UBC in the Department of Physics and Astronomy since 2001

Appointed as the Canada Research Chair in Theoretical Molecular Biophysics

Associate member of the Genome Sciences and Technology Program, the

Bioinformatics Program, and the Institute for Applied Mathematics at the

University of British Columbia

Founding Managing Director of Danforth Advisors

Served as the Chief financial officer of Homology, Inc, GenePeeks,

Inc., Transkaryotic Therapies, Inc., Cidara, Inc., Apellis, Inc. and

Stealth BioTherapeutics, Inc.

Former VP of Research at Genzyme

Associate Immunopathologist at SmithKline Beecham where she

established an Immunotoxicology program

Her work has resulted in over 60 scientific publications and multiple patents

Gene Williams

Elliot Goldstein

Neil Cashman

Steven Plotkin

Dan Geffken

Johanne Kaplan

James Kupiec Chief Medical Officer 25+

Former VP, Global Clinical Leader for Parkinson’s disease, and Clinical Head

of the Neuroscience Research Unit for Pfizer, Inc

Clinical focus on development of therapies for neurodegenerative disorders

Held positions at Sanofi-Synthelabo and Ciba-Geigy Pharmaceuticals

Richard Gregory

Bill Wyman

Johannes Roth

Pat Kirwin

66

Independent board of directors

31

Prior ExperienceYears of Experience

25+

15+

40+

Chief Scientific Officer & Executive VP for Research

at ImmunoGen

Held a variety of roles at Genzyme and Sanofi-

Genzyme, including Vice President for Gene

Therapy, Head of Corporate Research and Head of

R&D

Co-founded the management consulting firm, Oliver

Wyman & Co

Former President of the Management Consulting

Group called Booz Allen and Hamilton

Founding director and partner at FiveT Capital

Holding AG

A board member of Insilico Biotechnology AG

Senior partner at Kirwin LLP

Advises and represents businesses in a range of

industries and sizes from local to multinational

30+

Name

Name

Scientific Advisory Board

32

Prior ExperienceYears of Experience

Todd Golde, MD, PhD

Lary Walker, PhD

Bill Mobley, MD, PhD

Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida

Associate Professor of Neurology and Research Professor at Emory University Yerkes

National Primate Research Center

Dean for Neurosciences Initiatives, Distinguished Professor of Neurosciences, and

Florence Riford Chair for Alzheimer Disease at the University of California, San Diego

20+

25+

20+

Sharon Cohen, MD 20+Medical Director & Principal Investigator of Toronto Memory Program

FRCPC in neurology from Royal College of Physicians of Canada and a fellowship in

Behavioural Neurology from the University of Toronto

Rudy Tanzi, PhD 20+Professor of Neurology at Harvard University, Vice Chair of Neurology, Director of

Genetics & Aging Research Unit, Co-Director McCance Center for Brain Health at Mass

General Hospital

C. Warren Olanow, MD 25+ Previous Henry P & Georgette Goldschmidt Professor & Chairman, Department of

Neurology at Mount Sinai School of Medicine, presently Professor Emeritus Department

of Neurology & Department of Neuroscience, CEO of CLINTREX

Affiliations

Andre Strydom, MD, PhD Professor Institute of Psychiatry, Psychology and Neuroscience at King’s College

London

Honorary Consultant psychiatrist, South London and the Maudsley NHS Foundation

Trust

25+

José Molinuevo, MD, PhD 20+ Scientific Director, Alzheimer Prevention Program at Barcelonaβeta Brain Research

Center, Barcelona Spain

Associate Professor, Pompeu Fabra University, Barcelona, Spain

Hans Frykman, MD, PhD 20+ Clinical assistant professor of medicine at the University of British ColumbiaCEO and Medical Director of BC Neuroimmunology Lab (BCNI)

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